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      Management of Uveitis-Related Choroidal Neovascularization: From the Pathogenesis to the Therapy

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      Journal of Ophthalmology
      Hindawi Publishing Corporation

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          Abstract

          Inflammatory choroidal neovascularization is a severe but uncommon complication of uveitis, more frequent in posterior uveitis such as punctate inner choroidopathy, multifocal choroiditis, serpiginous choroiditis, and Vogt-Koyanagi-Harada syndrome. Its pathogenesis is supposed to be similar to the wet age related macular degeneration: hypoxia, release of vascular endothelial growth factor, stromal cell derived factor 1-alpha, and other mediators seem to be involved in the uveitis-related choroidal neovascularization. A review on the factors implicated so far in the pathogenesis of inflammatory choroidal neovascularization was performed. Also we reported the success rate of single studies concerning the therapies of choroidal neovascularization secondary to uveitis during the last decade: photodynamic therapy, intravitreal bevacizumab, and intravitreal ranibizumab, besides steroidal and immunosuppressive therapy. Hereby a standardization of the therapeutic approach is proposed.

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          Most cited references61

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          Processing of VEGF-A by matrix metalloproteinases regulates bioavailability and vascular patterning in tumors

          Vascular endothelial growth factor (VEGF) is a critical mediator of blood vessel formation during development and in pathological conditions. In this study, we demonstrate that VEGF bioavailability is regulated extracellularly by matrix metalloproteinases (MMPs) through intramolecular processing. Specifically, we show that a subset of MMPs can cleave matrix-bound isoforms of VEGF, releasing soluble fragments. We have mapped the region of MMP processing, have generated recombinant forms that mimic MMP-cleaved and MMP-resistant VEGF, and have explored their biological impact in tumors. Although all forms induced similar VEGF receptor 2 phosphorylation levels, the angiogenic outcomes were distinct. MMP-cleaved VEGF promoted the capillary dilation of existent vessels but mediated a marginal neovascular response within the tumor. In contrast, MMP-resistant VEGF supported extensive growth of thin vessels with multiple and frequent branch points. Our findings support the view that matrix-bound VEGF and nontethered VEGF provide different signaling outcomes. These findings reveal a novel aspect in the regulation of extracellular VEGF that holds significance for vascular patterning.
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            Pigment epithelium-derived factor (PEDF) and vascular endothelial growth factor (VEGF) in aged human choroid and eyes with age-related macular degeneration.

            The purpose of this study was to examine the localization and relative levels of vascular endothelial growth factor (VEGF; an angiogenic factor) and pigment epithelium-derived factor (PEDF; an antiangiogenic factor) in aged human choroid and to determine if the localization or their relative levels changed in age-related macular degeneration (AMD). Ocular tissues were obtained from eight aged control donors (age range, 75-86 years; mean age, 79.8 years) with no evidence or history of chorioretinal disease and from 12 donors diagnosed with AMD (age range, 61-105 years; mean age, 83.9 years). Tissues were cryopreserved and streptavidin alkaline phosphatase immunohistochemistry was performed with rabbit polyclonal anti-human VEGF and rabbit polyclonal anti-human PEDF antibodies. Binding of the antibodies was blocked by preincubation of the antibody with an excess of recombinant human PEDF or VEGF peptide. Choroidal blood vessels were identified with mouse anti-human CD-34 antibody in adjacent tissue sections. Three independent observers graded the immunohistochemical reaction product. The most prominent sites of VEGF and PEDF localization in aged control choroid were RPE-Bruch's membrane-choriocapillaris complex including RPE basal lamina, intercapillary septa, and choroidal stroma. There was no significant difference in immunostaining intensity and localization of VEGF and PEDF in aged control choroids. The most intense VEGF immunoreactivity was observed in leukocytes within blood vessels. AMD choroid had a similar pattern and intensity of VEGF immunostaining to that observed in aged controls. However, PEDF immunoreactivity was significantly lower in RPE cells (p=0.0073), RPE basal lamina (p=0.0141), Bruch's membrane (p<0.0001), and choroidal stroma (p=0.0161) of AMD choroids. The most intense PEDF immunoreactivity was observed in disciform scars. Drusen and basal laminar deposits (BLDs) were positive for VEGF and PEDF. In aged control subjects, VEGF and PEDF immunostaining was the most intense in RPE-Bruch's membrane-choriocapillaris complex. In AMD, PEDF was significantly lower in RPE cells, RPE basal lamina, Bruch's membrane and choroidal stroma. These data suggest that a critical balance exists between PEDF and VEGF, and PEDF may counteract the angiogenic potential of VEGF. The decrease in PEDF may disrupt the balance and be permissive for the formation of choroidal neovascularization (CNV) in AMD.
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              The binding of vascular endothelial growth factor to its receptors is dependent on cell surface-associated heparin-like molecules.

              Vascular endothelial growth factor (VEGF) induces the proliferation of endothelial cells and is a potent angiogenic factor that binds to heparin. We have therefore studied the effect of heparin upon the interaction of VEGF with its receptors. Heparin, at concentrations ranging from 0.1 to 10 micrograms/ml, strongly potentiated the binding of 125I-VEGF to its receptors on endothelial cells. Scatchard analysis of 125I-VEGF binding indicates that 1 microgram/ml heparin induces an 8-fold increase in the apparent density of high affinity binding sites for VEGF, but does not significantly affect the dissociation constant of VEGF. Cross-linking experiments showed that heparin strongly potentiates the formation of the 170-, 195- and 225-kDa 125I-VEGF-receptor complexes on endothelial cells. At high 125I-VEGF concentrations (4 ng/ml), heparin preferentially enhanced the formation of the 170- and 195-kDa complexes. Preincubation of the cells with heparin, followed by extensive washes, produced a similar enhancement of subsequent 125I-VEGF binding. The binding of 125I-VEGF was completely inhibited following digestion of endothelial cells with heparinase and could be restored by the addition of exogenous heparin to the digested cells. The enhancing effect of heparin facilitated the detection of VEGF receptors on cell types that were not known previously to express such receptors. Our results suggest that cell surface-associated heparin-like molecules are required for the interaction of VEGF with its cell surface receptors.
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                Author and article information

                Journal
                J Ophthalmol
                J Ophthalmol
                JOPH
                Journal of Ophthalmology
                Hindawi Publishing Corporation
                2090-004X
                2090-0058
                2014
                27 April 2014
                : 2014
                : 450428
                Affiliations
                Department of Ophthalmology, “Sapienza” University of Rome, Viale del Policlinico 155, 00161 Rome, Italy
                Author notes

                Academic Editor: Vishali Gupta

                Author information
                http://orcid.org/0000-0002-1009-3613
                Article
                10.1155/2014/450428
                4020300
                24868454
                953912d8-6284-4359-86d7-e6bf16d53e0d
                Copyright © 2014 Enzo D'Ambrosio et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 21 December 2013
                : 10 April 2014
                Categories
                Review Article

                Ophthalmology & Optometry
                Ophthalmology & Optometry

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